In recent years a large body of research evidence has accumulated supporting the concept that AIDS is an immunological disease induced by HIV-1 rather than simply being caused by loss of CD4+T-lymphocytes as a result of chronic cytopathic viral infection. It is therefore important to develop interventions that also target the chronic immune stimulation induced by HIV-1.
Previous research shows that antibodies to the carboxyterminal C5 domain of HIV-1 gp120 has been associated with lower immune activation and slower disease progression (Loomis-Price et al. 1998 J. Inf Dis. 178:1306-1316; Warren R Q wt al. 1991 J. Clin Immunol 11: 13-21; Lifson et al. 1991 J. Inf. Dis 163:959-965). Indeed, disease progression was shown to accelerate if humoral (i.e antibody) responses to this domain were lost (Wong et al. 1993 J. Inf. Dis 168: 1523-1527). Furthermore long term nonprogressors (LTNP) which represent 5% of HIV-infected individuals have sustained humoral responses to the carboxyterminal C5 domain of HIV-1 gp120 and can live in the absence of antiretroviral therapy for many years despite having some degree of viral load (Liegler et al. 1998 J. Infec. Dis. 178: 669-79; Gougeon et al. 1996 J. Immuno) 156:3509-20; Muro-Cacho et al. 1995 J. Immunol 154:5555-66; Easterbrook et al. 1999 J. Infect 28:71-73).
The C5 domain of gp120 is 13 amino acids long (amino acid residues 499-511 of gp120, and has the reference sequence B.FR 83.HXB2-TKAKRRVVQREKR). Its conservation across multiple virus clades is shown in Table 1. The only regions that show any substantial variation are at positions 500 and 507 of the sequence which may contain predominantly amino acids K, R and E at position (500) or predominantly Q, E at position (506).
TABLE 1(C5-domain for different multiple clades)C5 SEQUENCESVIRAL CLADES (%)Residues 497-511AA1A2BCDAPTKAKRRVVQREKR3.1%//58.3%0.7%/(SEQ ID NO: 47) APTKAKRRVVEREKR21.9%12.8%//23.5%33.0%(SEQ ID NO: 48) APTRAKRRVVQREKR3.1%//12.4%/1.7%(SEQ ID NO: 49) APTRAKRRVVEREKR15.6%27.7%33.3%/3.0%33.3%(SEQ ID NO: 50) APTEAKRRVVEREKR////16.8%3.3%(SEQ ID NO: 51) 43.7%40.5%33.3%70.7%44.0%68.3%
The table provided is based on 1066 sequences downloaded from the Los Alamos HIV-database 3rd of May 2008.
The sequences grouped in the following viral clades:
A: 32 sequences, A1: 47 sequences, A2: 10 sequences, B: 453 sequences, C: 464 sequences, and D: 60 sequences.
This carboxyterminal constant region C5 of HIV-1 gp120 is immunodominant and highly conserved across multiple HIV subtypes. It is exposed on the 3D structure of native gp120, on virions and on cell surface expressed gp120. Indeed, the C5 domain resembles human leukocyte antigen (HLA) classes I and II molecules and has the ability to bind peptides and deletion of the C5 domain abrogates peptide binding (Cadogan et al. AIDS Research and Human Retorviruses (2008); Vol. 24: 845-855). In this way the C5 domain can mimic the activities of human HLA.
However, to date the mechanisms behind C5-associated immune activation are currently largely unknown, meaning that it has been impossible to rationally devise drugs and diagnostic/prognostic means based on these mechanisms.